This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The human immunodeficiency virus type 1 (HIV) gains access to the central nervous system (CNS) early in the course of infection. Nevertheless, dementia due to HIV (HIV-D), seen in about 15% of HIV+ individuals, is a relatively late manifestation of the illness occurring usually in the context of a severely immunocompromised state and a high viral load. Once HIV has transgressed the blood-brain barrier (BBB), the potential exists for unchecked replication within the brain, even after peripheral viral levels have been reduced to undetectable levels by highly active antiretroviral therapy (HAART). Therapeutic failures with HAART occur in about 50% of patients and new cases of HIV dementia are still developing. It is unclear as to what extent dementia arises due to reseeding of the brain late in the disease or to what extent subcortical or neocortical structures contribute to dementia. Are there markers that could be measured noninvasively that reflect changes in CNS viral load and the attendant brain injury? Is there a marker that could be assessed easily that reflects a developing resistance to HAART? Can the temporal course of regional brain injury be mapped in the brain, noninvasively? Magnetic resonance spectroscopy (MRS) is a noninvasive tool with easy reproducibility that measures brain metabolites, reflecting CNS function. We intend to address these questions in humans using MRS and MRS imaging (MRSI), proposing that brain metabolite concentrations may serve as surrogate markers of CNS HIV activity. Concurrent assessment of CNS immune activation, BBB integrity and viral load through measurement of appropriate CSF and peripheral markers would further enhance understanding of viral CNS activity in vivo, and the ability for that activity to continue to engender dementia even during HAART. The broad objectives of the proposed research are to determine a) how the level of HIV-related CNS activity, as measured by MRS and MRSI, can be correlated to neurological status and b) whether brain metabolite levels reflect the adequacy of therapy at keeping HIV in check in the CNS. This R01 relates specifically to project 2 proposed in this resource application. Since patients with HIV dementia are uncomfortable in the MR scanner for long periods of time, the development of fast MRSI techniques are of critical importance to this project. Also, the comfortable environment of the Kennedy Krieger Institute F.M. Kirby Center for Functional Brain Imaging, in particular the short and wide bore of the magnets, will ensure maximum possible patient compliance in this study. A second area of technical development (project 2) is the development of short echo time MRSI techniques, so that quantitative mapping of myo-inositol will be possible. It has previously been shown using single voxel techniques that myo-inositol is one of the most important metabolites for the detection of early CNS abnormalities in HIV infection.
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